{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T13:08:58Z","timestamp":1781096938621,"version":"3.54.1"},"reference-count":85,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T00:00:00Z","timestamp":1766102400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005357","name":"Slovak Research and Development Agency","doi-asserted-by":"publisher","award":["APVV-21-0108"],"award-info":[{"award-number":["APVV-21-0108"]}],"id":[{"id":"10.13039\/501100005357","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>In this study, new improved inhibitors of the viral enzyme 3-chymotrypsin-like protease (3CLpro) were designed using structure-based drug design techniques in an effort to discover more effective treatment of coronavirus disease 2019 (COVID-19). Three-dimensional models of 3CLpro\u2013inhibitor complexes were prepared by in situ modification of the crystal structure of the submicromolar covalent inhibitor IPCL6 for a set of 25 known inhibitors with published inhibitory potencies (IC50exp). The QSAR model was prepared with a reasonable correlation between the calculated free energies of formation of the 3CLpro-IPCL complex (\u2206\u2206Gcom) and the experimentally determined activities IC50exp, which explained approximately 92% of the variation in the 3CLpro inhibition data. A similar agreement was achieved for the QSAR pharmacophore model (PH4) built on the basis of the active conformations of the IPCL inhibitors bound at the active site of the 3CLpro. The virtual combinatorial library of more than 567,000 IPCL analogues was screened in silico using the PH4 model and resulted in the identification of 39 promising analogues. The best inhibitors designed in this study show high predicted affinity for the 3CLpro protease, as well as favourable predicted ADME properties. For the best new virtual inhibitor candidate IPCL 80-27-74-4, the inhibitory concentration IC50pre was predicted equal to 0.8 nM, which represents a significant improvement in the inhibitory potency of known IPCLs. Ultimately, molecular dynamics simulations of the 12 newly designed top-scoring IPCL inhibitors demonstrated that the 3CLpro\u2013inhibitor complexes exhibited good structural stability, confirming the potential for further development of the designed IPCL analogues.<\/jats:p>","DOI":"10.3390\/life16010006","type":"journal-article","created":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T12:59:57Z","timestamp":1766149197000},"page":"6","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["In Silico Optimization of Inhibitors of the 3-Chymotrypsin-like Protease of SARS-CoV-2"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-9000-9224","authenticated-orcid":false,"given":"Issouf","family":"Fofana","sequence":"first","affiliation":[{"name":"Laboratoire de Physique Fondamentale et Appliqu\u00e9e (LPFA), University of Abobo Adjam\u00e9 (Now Nangui Abrogoua), 02 BP 801, Abidjan 02, C\u00f4te d\u2019Ivoire"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7326-8971","authenticated-orcid":false,"given":"Brice","family":"Dali","sequence":"additional","affiliation":[{"name":"Laboratoire des Sciences de la Mati\u00e8re de l\u2019Environnement et de l\u2019\u00e9nergie Solaire (LASMES), UFR SSMT Universit\u00e9 F\u00e9lix Houphou\u00ebt Boigny, 22 BP 582, Abidjan 22, C\u00f4te d\u2019Ivoire"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5771-1789","authenticated-orcid":false,"given":"Mawa","family":"Kon\u00e9","sequence":"additional","affiliation":[{"name":"Laboratoire de Constitution et de R\u00e9action de la Mati\u00e8re (LCRM), UFR SSMT Universit\u00e9 F\u00e9lix Houphou\u00ebt Boigny, 22 BP 582, Abidjan 22, C\u00f4te d\u2019Ivoire"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2915-7485","authenticated-orcid":false,"given":"Katarina","family":"Sujova","sequence":"additional","affiliation":[{"name":"Department of Physical Chemistry of Drugs, Faculty of Pharmacy, Comenius University Bratislava, SK-83232 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1505-5277","authenticated-orcid":false,"given":"Eugene","family":"Megnassan","sequence":"additional","affiliation":[{"name":"Laboratoire de Physique Fondamentale et Appliqu\u00e9e (LPFA), University of Abobo Adjam\u00e9 (Now Nangui Abrogoua), 02 BP 801, Abidjan 02, C\u00f4te d\u2019Ivoire"},{"name":"Laboratoire des Sciences de la Mati\u00e8re de l\u2019Environnement et de l\u2019\u00e9nergie Solaire (LASMES), UFR SSMT Universit\u00e9 F\u00e9lix Houphou\u00ebt Boigny, 22 BP 582, Abidjan 22, C\u00f4te d\u2019Ivoire"},{"name":"Laboratoire de Constitution et de R\u00e9action de la Mati\u00e8re (LCRM), UFR SSMT Universit\u00e9 F\u00e9lix Houphou\u00ebt Boigny, 22 BP 582, Abidjan 22, C\u00f4te d\u2019Ivoire"},{"name":"International Centre for Applied Research and Sustainable Technology, SK-84104 Bratislava, Slovakia"},{"name":"International Centre for Theoretical Physics, ICTP-UNESCO, Strada Costiera, I-34151 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6766-4571","authenticated-orcid":false,"given":"Stanislav","family":"Miertus","sequence":"additional","affiliation":[{"name":"International Centre for Applied Research and Sustainable Technology, SK-84104 Bratislava, Slovakia"},{"name":"Department of Biotechnologies, Faculty of Natural Sciences, University of Ss. 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